Thia-triaza-indacenes

ABSTRACT

The present invention encompasses compounds of general formula (1) wherein R 1  to R 3  and X are defined as in claim  1 , which are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation, and the use thereof for preparing a medicament having the above-mentioned properties.

The present invention relates to new thia-triaza-indacenes of generalformula (1)

wherein the groups R¹ to R³ and X have the meanings given in the claimsand specification, the isomers thereof, processes for preparing thesethia-triaza-indacenes and their use as medicaments.

BACKGROUND TO THE INVENTION

A number of protein kinases have already proved to be suitable targetmolecules for therapeutic intervention in a variety of indications, e.g.cancer and inflammatory and autoimmune diseases. Since a high percentageof the genes involved in the development of cancer which have beenidentified thus far encode kinases, these enzymes are attractive targetmolecules for the therapy of cancer in particular.

Phosphatidylinositol-3-kinases (PI3-kinases) are a subfamily of thelipid kinases which catalyse the transfer of a phosphate group to the3′-position of the inositol ring of phosphoinositides.

They play an important role in numerous cell processes such as e.g. cellgrowth and differentiation processes, the control of cytoskeletalchanges and the regulation of intracellular transport processes. On thebasis of their in vitro specificity for certain phosphoinositidesubstrates the PI3-kinases can be divided into different categories.

Thiazolyl-dihydro-indazoles are described for example as kinasesinhibiting compounds in WO2006040279 and WO2006040281.

DETAILED DESCRIPTION OF THE INVENTION

It has now surprisingly been found that compounds of general formula(1), wherein the groups R¹ to R³ and X have the meanings given below,act as inhibitors of specific kinases. Thus, the compounds according tothe invention may be used for example for the treatment of diseasesconnected with the activity of specific kinases and characterised byexcessive or abnormal cell proliferation.

The present invention relates to compounds of general formula (1)

wherein

X is a substituted C2-alkylidene chain; or

X is an optionally substituted C2-alkylidene chain wherein one or twomethylene units are independently from one another replaced by C(O),NR^(g)C(O), SO, SO₂, NR^(g)SO₂, O, S, or NR^(g); and wherein thesubstituents are independently from one another selected from R^(f) andR^(g); and

R¹ denotes hydrogen or R⁴; and

R² denotes hydrogen or R⁵; and

R³ denotes hydrogen or R⁶; and

each R⁴, R⁵ and R⁶ independently of one another denotes a group selectedfrom among R^(a), R^(b) and R^(a) substituted by one or more identicalor different R^(b) and/or R^(c); and

each R^(a) independently of one another denotes a group optionallysubstituted by one or more identical or different R^(b) and/or R^(c),selected from among C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, 2-6 memberedheteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl,C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 membered heteroaryl, 6-18 memberedheteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 memberedheterocycloalkylalkyl,

each R^(b) denotes a suitable group and is selected independently of oneanother from among ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S,—SR^(c), ═NR^(c), ═NOR^(c), ═NNR^(c)R^(c), ═NN(R^(g))C(O)NR^(c)R^(c),—NR^(c)R^(c), —ONR^(c)R^(c), —N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c),halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c),—S(O)OR^(c), —S(O)₂R^(c), —S(O)₂OR^(c), —S(O)NR^(c)R^(c),—S(O)₂NR^(c)R^(c), —OS(O)R^(c), —OS(O)₂R^(c), —OS(O)₂OR^(c),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(c), —C(O)OR^(c),—C(O)SR^(c), —C(O)NR^(c)R^(c), —C(O)N(R^(g))NR^(c)R^(c),—C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c), —C(NOH)R^(c),—C(NOH)NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —OC(O)SR^(c),—OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c), —SC(O)OR^(c),—SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c), —N(R^(g))C(O)R^(c),—N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c), —N(R^(g))C(NR^(g))R^(c),—N(R^(g))N(R^(g))C(O)R^(c), —N[C(O)R^(c)]NR^(c)R^(c),—N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c), —N(R^(g))S(O)OR^(c),—N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂, —N(R^(g))S(O)₂OR^(c),—N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c),—N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(c)OR^(c), —N(R^(g))C(O)NR^(g)NR^(c)R^(c),—N(R^(g))N(R^(g))C(O)NR^(c)R^(c), —N(R^(g))C(S)NR^(c)R^(c),—[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c), —N{[C(O)]₂R^(c)}₂,—N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c), —N{[C(O)]₂OR^(c)}₂,—N{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c),—N(R^(g))C(NR^(g))SR^(c), —N(R^(g))C(NR^(g))NR^(c)R^(c), —N═R^(c) and—N═C(R^(g))NR^(c)R^(c) and

each R^(c) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(d)and/or R^(e), selected from among C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,2-6 membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedheteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and

each R^(d) denotes a suitable group and is selected independently of oneanother from among ═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S,—SR^(e), ═NR^(e), ═NOR^(e), ═NNR^(e)R^(e), ═NN(R^(g))C(O)NR^(e)R^(e),—NR^(e)R^(e), —ONR^(e)R^(e), —N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN,—NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e),—S(O)₂R^(e), —S(O)₂OR^(e), —S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)₂OR^(e), —OS(O)NR^(e)R^(e),—OS(O)₂NR^(e)R^(e), —C(O)R^(e), —C(O)OR^(e), —C(O)SR^(e),—C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e), —C(O)N(R^(g))OR^(e),—C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e), —C(NOH)NR^(e)R^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)SR^(e), —OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e),—SC(O)R^(e), —SC(O)OR^(e), —SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e),—N(R^(g))C(O)R^(e), —N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e),—N(R^(g))C(NR^(g))R^(e), —N(R^(g))N(R^(g))C(O)R^(e),—N[C(O)R^(e)]NR^(e)R^(e), —N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e),—N(R^(g))S(O)OR^(e)—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂,—N(R^(g))S(O)₂OR^(e), —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),—N(R^(g))C(O)OR^(e), —N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(e)OR^(e), —N(R^(g))C(O)NR^(g)NR^(e)R^(e),—N(R^(g))N(R^(g))C(O)NR^(e)R^(e), —N(R^(g))C(S)NR^(e)R^(e),—[N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e), —N{[C(O)]₂R^(e)}₂,—N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e), —N{[C(O)]₂OR^(e)}₂,—N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e),—N(R^(g))C(NR^(g))SR^(e), —N(R^(g))C(NR^(g))NR^(e)R^(e), —N═R^(e)R^(e)and —N═C(R^(g))NR^(e)R^(e)

each R^(e) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(f)and/or R^(g), selected from among C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,2-6 membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cyclo alkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedheteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and

each R^(f) denotes a suitable group and in each case is selectedindependently of one another from among ═O, —OR^(g), C₁₋₃haloalkyloxy,—OCF₃, —OCHF₂, ═S, —SR^(g), ═NR^(g), ═NOR^(g), ═NNR^(g)R^(g),═NN(R^(h))C(O)NR^(g)R^(g), —NR^(g)R^(g), —ONR^(g)R^(g),—N(R^(h))NR^(g)R^(g), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(g), —S(O)OR^(g), —S(O)₂R^(g), —S(O)₂OR^(g),—S(O)NR^(g)R^(g), —S(O)₂NR^(g)R^(g), —OS(O)R^(g), —OS(O)₂R^(g),—OS(O)₂OR^(g), —OS(O)NR^(g)R^(g), —OS(O)₂NR^(g)R^(g), —C(O)R^(g),—C(O)OR^(g), —C(O)SR^(g), —C(O)NR^(g)R^(g), —C(O)N(R^(h))NR^(g)R^(g),—C(O)N(R^(h))OR^(g), —C(NR^(h))NR^(g)R^(g), —C(NOH)R^(g),—C(NOH)NR^(g)R^(g), —OC(O)R^(g), —OC(O)OR^(g), —OC(O)SR^(g),—OC(O)NR^(g)R^(g), —OC(NR^(h))NR^(g)R^(g), —SC(O)R^(g), —SC(O)OR^(g),—SC(O)NR^(g)R^(g), —SC(NR^(h))NR^(g)R^(g), —N(R^(h))C(O)R^(g),—N[C(O)R^(g)]₂, —N(OR^(h))C(O)R^(g), —N(R^(h))C(NR^(h))R^(g),—N(R^(h))N(R^(h))C(O)R^(g), —N[C(O)R^(g)]NR^(g)R^(g),—N(R^(h))C(S)R^(g), —N(R^(h))S(O)R^(g), —N(R^(h))S(O)OR^(g),—N(R^(h))S(O)₂R^(g), —N[S(O)₂R^(g)]₂, —N(R^(h))S(O)₂OR^(g),—N(R^(h))S(O)₂NR^(g)R^(g), —N(R^(h))[S(O)₂]₂R^(g), —N(R^(h))C(O)OR^(g),—N(R^(h))C(O)SR^(g), —N(R^(h))C(O)NR^(g)R^(g),—N(R^(h))C(O)NR^(g)OR^(g), —N(R^(h))C(O)NR^(h)NR^(g)R^(g),—N(R^(h))N(R^(h))C(O)NR^(g)R^(g), —N(R^(h))C(S)NR^(g)R^(g),—[N(R^(h))C(O)]₂R^(g), —N(R^(h))[C(O)]₂R^(g), —N{[C(O)]₂R^(g)}₂,—N(R^(h))[C(O)]₂OR^(g), —N(R¹¹)[C(O)]₂NR^(g)R^(g), —N{[C(O)]₂OR^(g)}₂,—N{[C(O)]₂NR^(g)R^(g)}₂, —[N(R^(h))C(O)]₂OR^(g),—N(R^(h))C(NR^(h))OR^(g), —N(R^(h))C(NOH)R^(g),—N(R^(h))C(NR^(h))SR^(g), —N(R^(h))C(NR^(h))NR^(g)R^(g), —N═R^(h)R^(h)and —N═C(R^(h))NR^(h)R^(h); and

each R^(g) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(h),selected from among C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, 2-6 memberedheteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl,C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 membered hetero aryl, 6-18 memberedheteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 memberedheterocycloalkylalkyl; and

each R^(h) is selected independently of one another from among hydrogen,C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, 2-6 membered heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl,3-14 membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl,

optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers, and the mixtures thereof, and optionally thepharmacologically acceptable salts thereof.

One aspect of the invention are compounds of general formula (1),wherein R³ is a radical selected from the group consisting of imidazol,pyrazole, triazol, furyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl andpyridazinyl, optionally substituted by one or more R⁶.

A further aspect of the invention are compounds of general formula (1),wherein R³ is pyridyl, optionally substituted by one or more R⁶.

A further aspect of the invention are compounds of general formula (1),wherein R³ is selected from —C(O)R^(c), —C(O)OR^(c) and—C(O)NR^(c)R^(c).

A further aspect of the invention are compounds of general formula (1),wherein R¹ is selected from among —NHR^(c), —NHC(O)R^(c), —NHC(O)OR^(c),—NHC(O)NR^(c)R^(c) and —NHC(O)N(R^(g))OR^(c).

A further aspect of the invention are compounds of general formula (1),wherein R² is selected from among C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 membered Heteroaryl,6-18 membered heteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14membered heterocycloalkylalkyl, optionally substituted by one or moreR⁵.

A further aspect of the invention are compounds of general formula (1),wherein X is a substituted C2 alkylidene chain.

A further aspect of the invention are compounds of general formula (1),wherein X is an optionally substituted C2 alkylidene chain, wherein onemethylene unit is replaced by O or S.

A further aspect of the invention are compounds of general formula(1)—or the pharmaceutically active salts thereof—for use as amedicament.

A further aspect of the invention are compounds of general formula(1)—or the pharmacologically effective salts thereof, for preparing amedicament with an antiproliferative activity.

A further aspect of the invention is a pharmaceutical preparation,containing as active substance one or more compounds of general formula(1) or the physiologically acceptable salts thereof optionally inconjunction with conventional excipients and/or carriers.

A further aspect of the invention is the use of a compound of generalformula (1) for preparing a pharmaceutical composition for the treatmentand/or prevention of cancer, infections, inflammatory and autoimmunediseases.

A further aspect of the invention is a pharmaceutical preparationcomprising a compound of general formula (1) and at least one othercytostatic or cytotoxic active substance, different from formula (1),optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

A further aspect of the invention are compounds of general formula (1A),(1B) or (1C)

wherein

R¹ denotes hydrogen or R⁴; and

R² denotes hydrogen or R⁵; and

R³ denotes hydrogen or R⁶; and

each R⁴, R⁵ and R⁶ independently of one another denotes a group selectedfrom among R^(a), R^(b) and R^(a) substituted by one or more identicalor different R^(b) and/or R^(c); and

each R^(a) independently of one another denotes a group optionallysubstituted by one or more identical or different R^(b) and/or R^(c),selected from among C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, 2-6 memberedheteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl,C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 membered heteroaryl, 6-18 memberedheteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 memberedheterocycloalkylalkyl,

each R^(b) denotes a suitable group and is selected independently of oneanother from among ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S,—SR^(c), ═NR^(c), ═NOR^(c), ═NNR^(c)R^(c), ═NN(R^(g))C(O)NR^(c)R^(c),—NR^(c)R^(c), —ONR^(c)R^(c), —N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c),halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c),—S(O)OR^(c), —S(O)₂R^(c), —S(O)₂OR^(c), —S(O)NR^(c)R^(c),—S(O)₂NR^(c)R^(c), —OS(O)R^(c), —OS(O)₂R^(c), —OS(O)₂OR^(c),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(c), —C(O)OR^(c),—C(O)SR^(c), —C(O)NR^(c)R^(c), —C(O)N(R^(g))NR^(c)R^(c),—C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c), —C(NOH)R^(c),—C(NOH)NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —OC(O)SR^(c),—OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c), —SC(O)OR^(c),—SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c), —N(R^(g))C(O)R^(c),—N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c), —N(R^(g))C(NR^(g))R^(c),—N(R^(g))N(R^(g))C(O)R^(c), —N[C(O)R^(c)]NR^(c)R^(c),—N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c), —N(R^(g))S(O)OR^(c),—N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂, —N(R^(g))S(O)₂OR^(c),—N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c),—N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(c)OR^(c), —N(R^(g))C(O)NR^(g)NR^(c)R^(c),—N(R^(g))N(R^(g))C(O)NR^(c)R^(c), —N(R^(g))C(S)NR^(c)R^(c),—[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c), —N{[C(O)]₂R^(c)}₂,—N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c), —N{[C(O)]₂OR^(c)}₂,—N{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c),—N(R^(g))C(NR^(g))SR^(c), —N(R^(g))C(NR^(g))NR^(c)R^(c), —N═R^(c) and—N═C(R^(g))NR^(c)R^(c) and

each R^(c) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(d)and/or R^(e), selected from among C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,2-6 membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedheteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and

each R^(d) denotes a suitable group and is selected independently of oneanother from among ═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, —OCHF₂, ═S,—SR^(e), ═NR^(e), ═NOR^(e), ═NNR^(e)R^(e), ═NN(R^(g))C(O)NR^(e)R^(e),—NR^(e)R^(e), —ONR^(e)R^(e), —N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN,—NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e),—S(O)₂R^(e), —S(O)₂OR^(e), —S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)₂OR^(e), —OS(O)NR^(e)R^(e),—OS(O)₂NR^(e)R^(e), —C(O)R^(e), —C(O)OR^(e), —C(O)SR^(e),—C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e), —C(O)N(R^(g))OR^(e),—C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e), —C(NOH)NR^(e)R^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)SR^(e), —OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e),—SC(O)R^(e), —SC(O)OR^(e), —SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e),—N(R^(g))C(O)R^(e), —N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(e),—N(R^(g))C(NR^(g))R^(e), —N(R^(g))N(R^(g))C(O)R^(e),—N[C(O)R^(e)]NR^(e)R^(e), —N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e),—N(R^(g))S(O)OR^(e)—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂,—N(R^(g))S(O)₂OR^(e), —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),—N(R^(g))C(O)OR^(e), —N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(e)OR^(e), —N(R^(g))C(O)NR^(g)NR^(e)R^(e),—N(R^(g))N(R^(g))C(O)NR^(e)R^(e), —N(R^(g))C(S)NR^(e)R^(e),—[N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e), —N{[C(O)]₂R^(e)}₂,—N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e), —N{[C(O)]₂OR^(e)}₂,—N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e),—N(R^(g))C(NR^(g))SR^(e), —N(R^(g))C(NR^(g))NR^(e)R^(e), —N═R^(e)R^(e)and —N═C(R^(g))NR^(e)R^(e)

each R^(e) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(f)and/or R^(g), selected from among C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl,2-6 membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedheteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and

each R^(f) denotes a suitable group and in each case is selectedindependently of one another from among ═O, —OR^(g), C₁₋₃haloalkyloxy,—OCF₃, —OCHF₂, ═S, —SR^(g), ═NR^(g), ═NOR^(g), ═NNR^(g)R^(g),═NN(R^(h))C(O)NR^(g)R^(g), —NR^(g)R^(g), —ONR^(g)R^(g),—N(R^(h))NR^(g)R^(g), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(g), —S(O)OR^(g), —S(O)₂R^(g), —S(O)₂OR^(g),—S(O)NR^(g)R^(g), —S(O)₂NR^(g)R^(g), —OS(O)R^(g), —OS(O)₂R^(g),—OS(O)₂OR^(g), —OS(O)NR^(g)R^(g), —OS(O)₂NR^(g)R^(g), —C(O)R^(g),—C(O)OR^(g), —C(O)SR^(g), —C(O)NR^(g)R^(g), —C(O)N(R^(h))NR^(g)R^(g),—C(O)N(R^(h))OR^(g), —C(NR^(h))NR^(g)R^(g), —C(NOH)R^(g),—C(NOH)NR^(g)R^(g), —OC(O)R^(g), —OC(O)OR^(g), —OC(O)SR^(g),—OC(O)NR^(g)R^(g), —OC(NR^(h))NR^(g)R^(g), —SC(O)R^(g), —SC(O)OR^(g),—SC(O)NR^(g)R^(g), —SC(NR^(h))NR^(g)R^(g), —N(R^(h))C(O)R^(g),—N[C(O)R^(g)]₂, —N(OR^(h))C(O)R^(g), —N(R^(h))C(NR^(h))R^(g),—N(R^(h))N(R^(h))C(O)R^(g), —N[C(O)R^(g)]NR^(g)R^(g),—N(R^(h))C(S)R^(g), —N(R^(h))S(O)R^(g), —N(R^(h))S(O)OR^(g),—N(R^(h))S(O)₂R^(g), —N[S(O)₂R^(g)]₂, —N(R^(h))S(O)₂OR^(g),—N(R^(h))S(O)₂NR^(g)R^(g), —N(R^(h))[S(O)₂]₂R^(g), —N(R^(h))C(O)OR^(g),—N(R^(h))C(O)SR^(g), —N(R^(h))C(O)NR^(g)R^(g),—N(R^(h))C(O)NR^(g)OR^(g), —N(R^(h))C(O)NR^(h)NR^(g)R^(g),—N(R^(h))N(R^(h))C(O)NR^(g)R^(g), —N(R^(h))C(S)NR^(g)R^(g),—[N(R^(h))C(O)]₂R^(g), —N(R^(h))[C(O)]₂R^(g), —N{[C(O)]₂R^(g)}₂,—N(R^(h))[C(O)]₂OR^(g), —N(R¹¹)[C(O)]₂NR^(g)R^(g), —N{[C(O)]₂OR^(g)}₂,—N{[C(O)]₂NR^(g)R^(g)}₂, —[N(R^(h))C(O)]₂OR^(g),—N(R^(h))C(NR^(h))OR^(g), —N(R^(h))C(NOH)R^(g),—N(R^(h))C(NR^(h))SR^(g), —N(R^(h))C(NR^(h))NR^(g)R^(g), —N═R^(h)R^(h)and —N═C(R^(h))NR^(h)R^(h); and

each R^(g) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(h),selected from among C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, 2-6 memberedheteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl,C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 membered hetero aryl, 6-18 memberedheteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 memberedheterocycloalkylalkyl; and

each R^(h) is selected independently of one another from among hydrogen,C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, 2-6 membered heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl,3-14 membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl,

optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers, and the mixtures thereof, and optionally thepharmacologically acceptable salts thereof.

One aspect of the invention are compounds of general formula (1A), (1B)or (1C), wherein R³ is a radical selected from the group consisting ofimidazol, pyrazole, triazol, furyl, oxazolyl, pyridyl, pyrazinyl,pyrimidinyl and pyridazinyl, optionally substituted by one or more R⁶.

A further aspect of the invention are compounds of general formula (1A),(1B) or (1C), wherein R³ is pyridyl, optionally substituted by one ormore R⁶.

A further aspect of the invention are compounds of general formula (1A),(1B) or (1C), wherein R³ is selected from —C(O)R^(c), —C(O)OR^(c) and—C(O)NR^(c)R^(c).

A further aspect of the invention are compounds of general formula (1A),(1B) or (1C), wherein R¹ is selected from among —NHR^(c), —NHC(O)R^(c),—NHC(O)OR^(c), —NHC(O)NR^(c)R^(c) and —NHC(O)N(R^(g))OR^(c).

A further aspect of the invention are compounds of general formula (1A),(1B) or (1C), wherein R² is selected from among C₁₋₆alkyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 membered Heteroaryl,6-18 membered heteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14membered heterocycloalkylalkyl, optionally substituted by one or moreR⁵.

A further aspect of the invention are compounds of general formula 1A),(1B) or (1C)—or the pharmaceutically active salts thereof—for use as amedicament.

A further aspect of the invention are compounds of general formula 1A),(1B) or (1C)— or the pharmacologically effective salts thereof—forpreparing a medicament with an anti-proliferative activity.

A further aspect of the invention is a pharmaceutical preparation,containing as active substance one or more compounds of general formula(1A), (1B) or (1C) or the physiologically acceptable salts thereofoptionally in conjunction with conventional excipients and/or carriers.

A further aspect of the invention is the use of a compound of generalformula (1A), (1B) or (1C) for preparing a pharmaceutical compositionfor the treatment and/or prevention of cancer, infections, inflammatoryand autoimmune diseases.

A further aspect of the invention is a pharmaceutical preparationcomprising a compound of general formula (1A), (1B) or (1C) and at leastone other cytostatic or cytotoxic active substance, different fromformula (1A), (1B) or (1C), optionally in the form of the tautomers, theracemates, the enantiomers, the diastereomers and the mixtures thereof,and optionally the pharmacologically acceptable acid addition saltsthereof.

The following Examples illustrate the present invention withoutrestricting its scope.

Intermediates A

General Procedure A1: Formation of Diketones from Acid Chlorides.

The monoketone is added to dry THF (e.g. 10 mmol in 90 mL solvent) andthe suspension is cooled to −78° C. under inert atmosphere. LiHMDS (3.4eq.) is slowly added to the reaction mixture so that the reactiontemperature is kept below −60° C. After completion of the addition, asolution of the acid chloride (1.2 eq.) in dry THF (about 2-2.5 M) isadded slowly. The reaction mixture is stirred overnight allowing it towarm to RT. For the workup the mixture is cooled to −20° C. and thereaction is quenched with diluted hydrochloric acid and phosphate buffer(22 g NaH₂PO₄, 87 g Na₂HPO₄, 530 mL H₂O) resulting in a final pH ofabout 6. Ethyl acetate is added and the organic layer is separated. Theaqueous phase is extracted three times with ethyl acetate, the combinedorganic phases are dried over MgSO₄, filtered and the solvent is removedunder reduced pressure. The remaining solid is triturated with MTBE. Theproduct may be used without further purification.

General Procedure A2: Formation of Diketones from Esters

The monoketone (1.0 eq.) is dissolved in DMSO (1 M solution) and NaOtBuor sodium tert.-pentoxide (3.0 eq.) is slowly added. The reactionmixture is stirred for 30 min at RT before the ester (1.1 eq.) is addedslowly. After completion of the addition the mixture is stirred for 4 hat RT, poured on ice and neutralized with saturated ammonium chloridesolution. The precipitate is filtered off, washed with water and driedunder vacuum at 40° C. overnight. Alternatively, the solvent isevaporated after completion of the reaction and the crude product may beused for the next step without further purification.

General Procedure A3: Formation of Diketones from Active Esters.

a) Formation of the Active Ester

Carboxylic acid (1.0 eq.) is dissolved in CH₂Cl₂, CDI (1.0 eq.) is addedand the reaction mixture is stirred at RT over night. The solvent isremoved in vacuo and the crude product is used without furtherpurification.

b) Formation of the Diketone

A 1 M solution of LiHMDS (3.e eq.) in THF is diluted with THF and theresulting solution is cooled to −10° C. under inert atmosphere. Themonoketone (1.0 eq.) is added in small portions so that the reactiontemperature is kept below −10° C. After stirring one additional hour at−10° C., a solution of the active ester (2.0 eq.) in THF is addedslowly. The reaction mixture is stirred over night allowing it to warmto RT. The reaction is quenched with a saturated solution of NH₄Cl inwater and the aqueous phase is extracted twice with CH₂Cl₂. The combinedorganic layers are dried over MgSO₄, filtered and the solvent is removedunder reduced pressure. The product is purified by NP- orRP-chromatography.

General Procedure A4: Nucleophilic Aromatic Substitution ofo-Fluoropyridines.

The o-fluoropyridine and an excess of the amine are dissolved in EtOH oriPrOH/THF (0.1-0.2 M) and the mixture is heated in the microwave at 100°C. for 30-60 min or alternatively the reaction mixture is stirred at RTfor 1-16 h. After completion of the reaction the solvent is removed invacuo and the product is either purified by chromatography (NP withMeOH/DCM or RP with ACN/H₂O) or used without further purification.

A-01) 2-Amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one

5,5-Dimethyl-cyclohexane-1,3-dione (201 g, 1.43 mol) and NaOAc (176 g,2.14 mol) are suspended in AcOH (2 L) and Br₂ (229 g, 1.43 mol) is addedin dropwise while maintaining the reaction temperature between 15 and20° C. After complete addition, the reaction is stirred at RT overnight.Thiourea (109 g, 1.43 mol) is added in portions and the reaction mixtureis heated at 100° C. for 1 h. After cooling to RT, the AcOH is removedin vacuo and the resulting crude product is diluted with water (1 L) andneutralized with an aqueous saturated NaHCO₃ solution. The resultingmixture is extracted with ethyl acetate (4×500 mL). The organic layer iswashed with brine (500 mL), dried over anhydrous Na₂SO₄ and the solventis evaporated in vacuo to give crude product. The crude product iswashed with water (1.5 L) to yield2-amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one (211 g, 75%yield).

¹H NMR: (400 MHz, DMSO-d₆) δ 5.69 (br s, 2H), 2.61 (s, 2H), 2.33 (s,2H), 1.06 (s, 6H).

A-02)3-(5,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-1,1-dimethyl-urea

To a solution of 2-amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one(151 g, 0.768 mol) in acetonitrile (5 L) are added CDI (249 g, 1.53 mol)and DBU (233 g, 1.53 mol). The reaction mixture is stirred overnight at100° C. Dimethylamine (310 g, 3.83 mol) is added at RT and the stirringis continued overnight at 100° C. After cooling to RT, the reactionmixture is concentrated in vacuo and the residue is poured into icewater. The pH of the mixture is adjusted to pH 5 with HCl (6 M). Theaqueous mixture is extracted with ethyl acetate (4×500 mL). The combinedorganic layers are washed with brine (500 mL) and dried over anhydrousNa₂SO₄. The solvent is evaporated in vacuo to give crude product. Thecrude product is washed with water to give3-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-1,1-dimethyl-urea(169 g, 82% yield).

¹H NMR: (400 MHz, DMSO-d₆) δ 11.28 (br s, 1H), 2.92 (s, 6H), 2.68 (s,2H), 2.32 (s, 2H), 1.06 (s, 6H).

A-03)N-(5,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide

2-Amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one (40.5 g, 0.206mol) and Ac₂O (400 mL) are heated at 100° C. for 4 h. After cooling toRT, the reaction mixture is concentrated in vacuo. The precipitatedsolid is collected by filtration and affordsN-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide(36.5 g, 75% yield).

¹H NMR: (400 MHz, DMSO-d₆) δ 12.54 (br s, 1H), 2.73 (s, 2H), 2.36 (s,2H), 2.14 (s, 3H), 1.01 (s, 6H).

A-04) 2-Amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one

A-04A) 2-Hydroxy-6-methyl-4-oxo-cyclohex-1-enecarboxylic acid methylester

To a freshly prepared solution of MeONa (432 g, 7.99 mol) in MeOH (2 L)is added 3-oxo-butyric acid ethyl ester (1.04 kg, 7.99 mol) over 15 minand the mixture is stirred on an ice bath for an additional 15 min.But-2-enoic acid ethyl ester (912 g, 7.99 mol) is added dropwise at RTand the mixture stirred at RT for 1 h and then the reaction mixture isrefluxed for 2 h. After cooling to RT, the precipitated solids arefiltered off, dissolved in cold water (1.5 L), acidified with HCl (3 M)to pH to 7 and the resulting mixture is extracted with EtOAc (4×800 mL).The combined organic phase is dried over anhydrous Na₂SO₄, the solventsare evaporated in vacuo and the residue recrystallized from hexane togive 2-hydroxy-6-methyl-4-oxo-cyclohex-1-enecarboxylic acid methyl ester(672 g, 42% yield).

¹H NMR: (400 MHz, DMSO-d₆) δ 11.39 (br s, 1H), 5.20 (s, 1H), 3.62 (s,3H), 3.10-3.08 (m, 1H), 2.35-2.20 (m, 3H), 0.930 (d, J=6.4 Hz, 3H).

A-04B) 5-Methyl-cyclohexane-1,3-dione

2-Hydroxy-6-methyl-4-oxo-cyclohex-1-enecarboxylic acid methyl ester (600g, 3.30 mol) is dissolved in NaOH solution (5 M, 3 L) and the solutionis refluxed for 2 h. After cooling to RT, the mixture is acidified withH₂SO₄ (5 M) to pH 7 and extracted with EtOAc (4×1 L). The organic phaseis washed with brine and dried over anhydrous Na₂SO₄. The solvent isevaporated and the residue is recrystallized from hexane to give5-methyl-cyclohexane-1,3-dione (200 g, 49% yield).

¹H NMR: (400 MHz, DMSO-d₆) δ 10.94 (br s, 1H), 5.14 (s, 1H), 2.30-2.18(m, 2H), 2.15-1.96 (m, 3H), 0.95 (d, J=6.4 Hz, 3H).

5-Methyl-cyclohexane-1,3-dione (70.0 g, 0.555 mol) and NaOAc (68.3 g,0.832 mol) are suspended in AcOH (700 mL) and Br₂ (88.7 g, 0.555 mol) isadded drop-wise while maintaining the reaction temperature between 15and 20° C. After complete addition, the reaction is stirred at RTovernight. Thiourea (42.2 g, 0.555 mol) is added in portions and thereaction mixture is heated to 100° C. for 1 h. After cooling to RT, theAcOH is removed in vacuo. The resulting crude product is diluted withwater (1 L), adjusted to pH=7 with NaHCO₃ solution (3 M) and theresulting mixture is extracted with EtOAc (3×1 L). The organic phase iswashed with brine and dried over anhydrous Na₂SO₄. The solvent isevaporated in vacuo and the residue is recrystallized from hexane togive 2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one (87.2 g, 86%yield).

¹H NMR: (400 MHz, DMSO-d₆) δ 8.09 (br s, 2H), 2.77-2.72 (m, 1H),2.39-2.13 (m, 4H), 1.03 (d, J=6.0 Hz, 3H).

A-05)1,1-Dimethyl-3-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-urea

To a solution of 2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one(30.0 g, 0.165 mol) in MeCN (750 mL) are added DBU (75.2 g, 0.495 mol)and CDI (80.1 g, 0.495 mol) at RT. The reaction mixture is stirred at110° C. overnight. Dimethylamine (93.5 g, 1.15 mol) and another portionof DBU (175 g, 1.15 mol) are added to the mixture at RT and the stirringis continued overnight at 110° C. After cooling to RT, the reactionmixture is evaporated in vacuo and the residue is poured into ice water.The reaction mixture is treated with HCl (6 M) to pH to 5. The aqueousmixture is extracted with EtOAc (3×300 mL). The combined organic phaseis washed with brine and dried over anhydrous Na₂SO₄. The solvent isevaporated and the residue is recrystallized from hexane to give1,1-dimethyl-3-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-urea(32.1 g, 77% yield).

¹H NMR: (400 MHz, DMSO-d₆) δ 11.38 (s, 1H), 2.86 (s, 6H), 2.85-2.84 (m,1H), 2.54-2.26 (m, 4H), 1.07 (d, J=6.0 Hz, 3H).

A-06) N-(5-Methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide

A solution of 2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one (25.0g, 0.137 mol) in Ac₂O (300 mL) is heated at reflux temperature for 3 h.The reaction mixture is then cooled to RT and the precipitate isfiltered off to affordN-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide.Yield: 26 g.

¹H NMR: (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 2.95-2.91 (m, 1H), 2.58-2.30(m, 5H), 2.17 (s, 3H), 1.07 (d, J=6.0 Hz, 3H).

A-07) 2-Amino-5-spirocyclopropyl-5,6-dihydro-4H-benzothiazol-7-one

The title compound is prepared analogously to2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one usingspiro[2.5]octane-5,7-dione (DE 102004061001) as starting material.HPLC-MS: t_(R)=0.43 min, (M+H)⁺=195.

A-08) 6-(tert-Butoxycarbonyl-ethyl-amino)-nicotinic acid

6-Chloro-nicotinic acid methyl ester (60 g, 0.35 mol) is taken up in 500mL 2 M ethylamine in THF and stirred at 100° C. in a sealed tube for 16h. The reaction mixture is cooled to RT and the solvents are removedunder reduced pressure. The residue is poured on ice and stirred for 15min. The precipitate is filtered off, washed with water and dried invacuo. The dried 6-ethylamino-nicotinic acid methyl ester (30 g, 0.17mol) is dissolved in 150 mL DCM and triethylamine (29 mL, 0.20 mol),DMAP (4.0 g, 33 mmol) and BOC anhydride (100 mL, 0.42 mol) are addedsuccessively at 0° C. The reaction mixture is allowed to warm up to RTand stirred for 16 h. To the reaction mixture 100 mL of 10% citric acidin water is added and the reaction mixture is stirred for 10 min. Theorganic phase is separated, dried over Na₂SO₄ and concentrated underreduced pressure.

Yield: 60 g.

The crude 6-(tert-butoxycarbonyl-ethyl-amino)-nicotinic acid methylester is taken up in 100 mL dioxane and a solution of lithium hydroxidemonohydrate (13.5 g, 0.32 mol) in 100 mL water is added and the reactionmixture is stirred at RT for 4 h. The dioxane is removed from thereaction mixture under reduced pressure, additional water is added andthe reaction mixture is acidified to pH 6 with a solution of 10% citricacid in water. The formed precipitate is filtered off and dried invacuo. Yield: 36 g.

¹H NMR (DMSO-d₆): δ 13.2 (s, 1H), 8.8 (s, 1H), 8.2 (d, 1H), 7.8 (d, 1H),4.0 (quart, 2H), 1.5 (s, 9H), 1.2 (t, 3H).

A-09) (5-Chlorocarbonyl-pyridin-2-yl)-ethyl-carbamic acid tert-butylester

6-(tert-Butoxycarbonyl-ethyl-amino)-nicotinic acid (6.40 g, 24.0 mmol)is taken up in 150 mL DCE, 1-chloro-N,N-2-trimethylpropenyl-amine (6.42mL, 48.1 mmol) is added and the reaction mixture is stirred overnight atRT. The reaction mixture is concentrated under reduced pressure and thecrude product is used in the next step without purification.

A-10) (5-Chlorocarbonyl-pyridin-2-yl)-methyl-carbamic acid tert-butylester

6-(tert-Butoxycarbonyl-methyl-amino)-nicotinic acid (12.5 g, 47.0 mmol)(prepared analogously to A-08 using methyl amine instead of ethylamine)is taken up in 300 mL DCE, 1-chloro-N,N-2-trimethylpropenyl-amine (10.0mL, 74.8 mmol) is added and the reaction mixture is stirred overnight atRT. The reaction mixture is concentrated under reduced pressure and thecrude product is used in the next step without purification.

A-11) 6-[N,N-Di-(tert-Butoxycarbonyl)-amino]-nicotinic acid

6-Amino-nicotinic acid methyl ester (13.7 g, 90.0 mmol), triethyl amine(12.5 mL, 90.0 mmol) and DMAP (3.30 g, 27.0 mmol) are taken up in 200 mLDCM and a solution of di-tert-butyl dicarbonate (41.3 g, 189 mmol) in 40mL DCM is added drop wise. The reaction mixture is stirred overnight atRT. An aqueous 5% KHSO₄ solution is added and the reaction mixture isextracted with DCM. The combined organic phases are washed with anaqueous 50% saturated KHCO₃ solution, dried over MgSO₄ and concentratedunder reduced pressure. Yield: 34.9 g.

Of this residue 17.3 g is taken up in a mixture of 150 mL MeOH and 300mL water, lithium hydroxide (2.33 g, 97.3 mmol) is added and thereaction mixture is stirred for 3 h at RT. The reaction mixture isacidified to pH 4 with acetic acid and the formed precipitate isfiltered off, washed with water and dried in vacuo. Yield: 11.8 g.

¹H NMR (DMSO-d₆): δ 9.0 (s, 1H), 8.2 (d, 1H), 7.2 (d, 2H), 1.4 (s, 18H).

A-12) N-tert-Butoxycarbonyl-(5-chlorocarbonyl-pyridin-2-yl)-carbamicacid tert-butyl ester

6-[N,N-Di-(tert-butoxycarbonyl)-amino]-nicotinic acid (5.00 g, 14.8mmol) is dried by azeotropic distillation with toluene and then taken upin 20 mL dry THF and cooled to 0° C.1-Chloro-N,N-2-trimethylpropenyl-amine (3.95 g, 30.0 mmol) is added dropwise and the reaction mixture is stirred at RT for 3 h. The reactionmixture is concentrated under reduced pressure and the crude product isused in the next step without purification.

A-13)[5-(2-Acetylamino-5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazole-6-carbonyl)-pyridin-2-yl]-methyl-carbamicacid tert-butyl ester

A-13 is prepared via general procedure A1 starting from(5-chlorocarbonyl-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester(A-10) (7.24 g, 26.8 mmol) andN-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (A-06)(5.00 g, 22.3 mmol). After evaporation of the solvent 7.72 g of A-13 isobtained that is used without further purification in the next step.

A-14)[5-(2-Acetylamino-5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazole-6-carbonyl)-pyridin-2-yl]-ethyl-carbamicacid tert-butyl ester

A-14 is prepared via general procedure A1 starting from(5-chlorocarbonyl-pyridin-2-yl)-ethyl-carbamic acid tert-butyl ester(A-09) (7.62 g, 26.8 mmol) andN-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (A-06)(5.00 g, 22.3 mmol). After evaporation of the solvent 8.62 g of A-14 areobtained which is used without further purification in the next step.

A-15)N-[5-Methyl-6-(6-methyl-pyridine-3-carbonyl)-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]acetamide

A-15 is prepared using general procedure A3 starting from A-06 (1.50 g,6.67 mmol) and methyl 6-methylnicotinate (1.10 g, 8.02 mmol). Thereaction is worked-up with DCM and the product is purified by flashcolumn chromatography (silicagel, 0-12% acetone in ethyl acetate) Yield:861 mg. HPLC-MS: t_(R)=1.43 min, (M+H)⁺=344.

A-16)N-[6-(6-Fluoro-pyridine-3-carbonyl)-5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]-acetamide

A-16 is prepared via general procedure A1 starting from2-fluoropyridine-5-carbonyl chloride (4.27 g, 26.8 mmol) andN-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (A-06)(5.00 g, 22.3 mmol). Yield: 6.20 g. HPLC-MS: t_(R)=0.93 min, (M+H)⁺=348.

A-17)2-Amino-6-(6-ethylamino-pyridine-3-carbonyl)-5-methyl-5,6-dihydro-4H-benzothiazol-7-one

To a suspension of 7.70 g (22.2 mmol) of A-16 in THF (50 mL)/isopropanol(50 mL) is added ethylamine (9.09 mL, 112 mmol). The reaction mixture isstirred for 3 d at RT and additional 4 h at 50° C. The solvent isremoved under reduced pressure and water and DCM are added to theresidue. After phase separation the organic layer is dried over sodiumsulfate and the solvent is removed under reduced pressure. The crudeproduct is purified by flash column chromatography (silicagel, 0-20%EtOH in DCM) yielding 6.60 g of A-17 as solid, which is used such as inthe next step.

A-18)[6-(6-Ethylamino-pyridine-3-carbonyl)-5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]-carbamicacid methyl ester

To a suspension of 2.00 g (6.05 mmol) of A-17 and1,1′-carbonyldiimidazole (2.46 g, 15.1 mmol) in 6 mL acetonitril isadded 1,8-diazabicyclo[5.4.0]undec-7-ene (1.8 mL, 12.1 mmol). Thereaction mixture is heated in the microwave for 10 min at 90° C. Ammoniain MeOH (951 μL, 7 M, 6.66 mmol) is added and heating is continued foranother 10 min at 120° C. Water and DCM are added to the reactionmixture and concentrated HCl (aq.) is added until pH 1 is reached. Afterphase separation the aqueous layer is extracted five times with DCM andethylacetate. The combined organic layers are dried over sodium sulfateand the solvent is removed under reduced pressure. Yield: 0.68 g.

HPLC-MS: t_(R)=0.90 min, (M+H)⁺=389.

A-19)[6-(6-Ethylamino-pyridine-3-carbonyl)-5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]-urea

To a suspension of 1.00 g (3.03 mmol) of A-17 and1,1′-carbonyldiimidazole (1.23 g, 7.57 mmol) in 10 mL acetonitril isadded 1,8-diazabicyclo[5.4.0]undec-7-ene (905 μL, 6.05 mmol). Thereaction mixture is heated in the microwave for 30 min at 120° C.Ammonium chloride (1.13 g, 21.2 mmol) is added and heating is continuedfor another 10 min at 120° C. Water and DCM are added to the reactionmixture and concentrated HCl (aq.) is added until pH 1 is reached. Afterphase separation the aqueous layer is washed three times with DCM. Theaqueous layer is evaporated under reduced pressure. The resultant crudemixture is used without further purification for the next step.

A-20)1-[6-(6-Ethylamino-pyridine-3-carbonyl)-5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]-3-methyl-urea

To a suspension of 1.00 g (3.03 mmol) of A-17 and1,1′-carbonyldiimidazole (1.20 g, 7.40 mmol) in 3 mL acetonitril isadded 1,8-diazabicyclo[5.4.0]undec-7-ene (696 μL, 4.54 mmol). Thereaction mixture is heated in the microwave for 10 min at 90° C.Methylamine in THF (3.33 mL, 6.65 mmol) is added and heating iscontinued for another 10 min at 120° C. Water and DCM are added to thereaction mixture and concentrated HCl (aq.) is added until pH 1 isreached. After phase separation the aqueous layer is washed three timeswith DCM. The aqueous layer is evaporated under reduced pressure. Theresultant crude mixture is taken up in DMSO/water and purified byreverse phase chromatography. Yield: 342 mg. HPLC-MS: t_(R)=0.90 min,(M+H)⁺=388.

A-21)N-[6-(6-Fluoro-pyridine-3-carbonyl)-5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]-acetamide

A-21 is prepared via general procedure A1 starting from 2-fluoropyridine-5-carbonyl chloride (1.00 g, 6.29 mmol) and A-03 (1.00 g, 4.20mmol). Yield: 1.30 g. which is used as such in the next step.

A-22)N-[6-(6-Amino-pyridine-3-carbonyl)-5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]-acetamide

To a solution of 2.00 g (5.53 mmol) of A-21 in THF (20 mL)/isopropanol(20 mL) is added an ammonia solution (27.6 mL, 32% in water, 221 mmol).The reaction mixture is stirred for 3 days at RT. The solvent is removedunder reduced pressure, water is added and the mixture is extractedthree times with ethylacetate. The combined organic layers are washedwith brine, dried over MgSO₄ and the solvent is removed under reducedpressure. The crude product is taken up is purified by reverse phasechromatography yielding 630 mg of the desired product as a crude whichis used as such in the next step.

A-23)1,1-Dimethyl-3-(5-spirocyclopropyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-urea

To a suspension of 1.05 (5.41 mmol) of A-07 and 1,1′-carbonyldiimidazole(1.75 g, 10.8 mmol) in 30 mL acetonitril is added1,8-diazabicyclo[5.4.0]undec-7-ene (1.62 mL, 10.8 mmol). The reactionmixture is stirred at 88° C. over night. The reaction mixture is cooleddown and dimethylamine in THF (18.9 mL, 2 M solution, 37.8 mmol) isadded and heating is continued for 20 min at 120° C. in the microwave.The solvent is removed under reduced pressure, water is added and pH isadjusted to 3-4 with 5 N HCl (aq.). The solution is extracted threetimes with ethylacetate. The combined organic layers are washed withbrine, dried over MgSO₄ and the solvent is removed under reducedpressure yielding 1.2 g of the desired product as a crude which is usedas such in the next step.

A-24)3-[5-Spirocyclopropyl-6-(6-fluoro-pyridine-3-carbonyl)-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]-1,1-dimethyl-urea

A-24 is prepared via general procedure A1 starting from 2-fluoropyridine-5-carbonyl chloride (1.44 g, 9.05 mmol) and A-23 (1.20 g, 4.52mmol). Yield: 2.00 g (crude) which is used as such in the next step.

A-25)3-[5-Spirocyclopropyl-6-(6-ethylamino-pyridine-3-carbonyl)-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl]-1,1-dimethyl-urea

To a solution of 1.00 g (1.54 mmol) of A-24 in THF (9 mL)/isopropanol (9mL) is added ethylamine in THF (5.79 mL, 2 M sol., 11.6 mmol). Thereaction mixture is stirred for 3 days at RT. The solvent is removedunder reduced pressure, water is added and the mixture is extractedthree times with ethylacetate. The combined organic layers are washedwith brine, dried over MgSO₄ and the solvent is removed under reducedpressure. The crude product is used as such in the next step.

A-26)(2-Acetylamino-5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-6-yl)-oxo-aceticacid methyl ester

To a stirred solution of A-06 (4.72 g, 20.0 mmol) in 75 ml DMF is addedsodium methylate (4.32 g, 80.0 mmol) under nitrogen at RT.Dimethyloxalate (4.77 g, 40.0 mmol) is added and stirring is continuedfor 3 h. The reaction mixture is cooled to 0° C., 100 mL water and 6.63mL concentrated HCl (aq.) are added carefully. The pH of the mixture isadjusted to pH 5 by the addition of potassium carbonate. Insolublematerial is filtered off, washed with water taken up inwater/acetonitril (v/v, 9/1) and freeze dried. Yield 3.00 g. (M−H)⁻=309.

A-27)7-Acetylamino-1-isopropyl-4-methyl-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazole-3-carboxylicacid

A mixture of B-34 (2.54 g, 7.29 mmol) and lithium hydroxide mono hydrate(776 mg, 18.2 mmol) in 30 mL dioxane and 30 mL water is stirred at 50°C. for 3 h. 1 M aqueous HCl solution is added to the reaction mixtureuntil pH 4 is reached. While the reaction mixture is allowed to cooldown a precipitation is formed. 50 mL water is added and most of thedioxane is evaporated under reduced pressure. The residue is filtered,washed twice with water (20 mL each) and freeze dried. Yield: 1.68 g.HPLC-MS: R_(t)=0.41 min, (M+H)⁺=335.

Examples B

Examples B-01 to B-34 are synthesized according to the following generalprocedure. The appropriate hydrazine and diketone required for synthesiscan be deduced from the table of examples.

General Procedure B:

The appropriate diketone (1 eq.) and the appropriate hydrazine orhydrazine salt (1-10 eq.) are added to acetic acid and heated to 60°C.-90° C. for 1-16 h. The acetic acid is removed under reduced pressureand the residue is taken up in water. The reaction mixture isneutralized to pH 5-6 with aqueous 10N NaOH and extracted with DCM. Thecombined organic phases are washed with water and brine, dried on MgSO₄and the solvents are removed under reduced pressure. The product may bepurified by NP or RP column chromatography.

TABLE 1 Examples B1-B34 No. MOLSTRUCTURE Diketone Hydrazine t_(R) (min.)(M + H)⁺ B1

A-15 cyclopentyl hydrazine 2.1 408 B2

A-15 isopropyl hydrazine 1.88 382 B3

A-15 o-tolyl hydrazine 1.93 430 B4

A-15 (1-cyclopropyl- piperidin-4-yl)- hydrazine 1.92 463 B5

A-18 tert-butyl hydrazine 1.71 441 B6

A-18 isopropyl hydrazine 1.49 427 B7

A-18 o-tolyl hydrazine 1.61 475 B8

A-18 2-fluoro-phenyl hydrazine 1.53 479 B9

A-20 isopropyl hydrazine 1.63 426 B10

A-20 o-tolyl hydrazine 1.71 474 B11

A-19 isopropyl hydrazine 1.57 410 [M − H] B12

A-19 o-tolyl hydrazine 1.65 460 B13

A-17 o-tolyl hydrazine 0.87 417 B14

A-14 o-tolyl hydrazine 1.67 459 B15

A-14 isopropyl hydrazine 1.59 411 B16

A-14 benzyl hydrazine 1.72 459 B17

A-14 pyridine-3yl- methyl hydrazine 1.41 460 B18

A-14 sec-butyl hydrazine 1.49 425 B19

A-14 (2,2,2)- trifluoroethyl hydrazine 1.45 451 B20

A-14 t-butyl hydrazine 1.31 369 B21

A-13 isopropyl hydrazine 1.56 397 B22

A-13 o-tolyl hydrazine 1.62 445 B23

A-13 benzyl hydrazine 1.62 445 B24

A-13 pyridine-3yl- methyl hydrazine 1.31 446 B25

A-13 sec-butyl hydrazine 1.63 411 B26

A-13 (tetrahydro- thiopyran-4-yl)- hydrazine 1.61 455 B27

A-13 (2,2,2)- trifluoroethyl hydrazine 1.47 437 B28

A-15 3-hydrazino- propionitrile 0.90 393 B29

A-15 2-fluoro-phenyl hydrazine 1.36 434 B30

A-15 2-hydrazino- ethanol 1.07 384 B31

A-22 o-tolyl hydrazine 1.42 445 B32

A-22 isopropyl hydrazine 1.32 397 B33

A-25 o-tolyl hydrazine 1.75 500 B34

A-26 isopropyl hydrazine 1.32 349

Examples C

Examples C-01 to C-23 are synthesized from example A-27 according to thefollowing general procedure. The appropriate amine required forsynthesis can be deduced from the table of examples.

General Procedure C:

The example A-27 (1 eq.) is taken up in DMA, DIPEA (2.5 eq.) and HATU(1.3 eq.) are added and the reaction mixture is stirred for 10 min atRT. Amine is added and the reaction mixture is stirred overnight at RTfollowed by 1 h at 55° C. The product is purified by HPLC (C18, 5-98%acetonitrile in water containing 0.1% formic acid).

TABLE 2 Examples C1-C23 No. MOLSTRUCTURE Amine t_(R) (min.) (M + H)⁺ C1

N,N,N′-trimethyl-ethane- 1,2-diamine 1.38 419 C2

benzyl-methyl-amine 1.78 438 C3

3-amino-propionic acid methyl ester 1.49 420 C4

4-amino-butyric acid ethyl ester 1.63 C5

benzyl-amine 1.78 424 C6

(2-methoxy-ethyl)-methyl- amine 1.39 406 C7

(3-methoxy-propyl)-methyl- amine 1.50 406 C8

(2-methoxy-ethyl)-amine 1.43 392 C9

ammonia 1.21 334 C10

N,N,N′-trimethyl-propane- 1,3-diamine 1.45 433 C11

2H-pyrazol-3-ylamine 1.38 400 C12

2-amino-N,N-dimethyl- acetamide 1.34 419 C13

dimethylamine 1.33 362 C14

N¹,N¹-dimethyl-ethane-1,2- diamine 1.42 405 C15

methylamine 1.50 348 C16

2-amino-ethanol 1.21 378 C17

3-amino-propanol 1.27 392 C18

N-methyl aniline 1.65 424 C19

2-methylamino-ethanol 1.18 392 C20

aniline 1.80 410 C21

3-methylamino-propanol 1.23 406 C22

N¹,N¹-dimethyl-propane- 1,3-diamine 1.52 419 C23

N,N-dimethyl-2- methylamino-acetamide 1.29 433

Intermediates D D-01)N-(7-Oxo-6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl)-acetamide

D-01A) Prop-2-ynyloxy-acetic acid ethyl ester

A solution of prop-2-yn-1-ol (815 g, 14.5 mol) in THF (1 L) is addeddropwise to a suspension of NaH (60% content) (500 g) in THF (4 L) at 0°C. under nitrogen atmosphere. The stirring is continued at thistemperature for 3 h before a solution of bromo-acetic acid ethylester(2.17 kg, 13.0 mol) in THF (2 L) is added dropwise over 1 h. Afteraddition, the temperature is allowed to warm to RT and the reactionmixture is stirred for another 3 h. HCl (2 M, 8 L) is added into thereaction mixture, the organic layer is isolated and the aqueous layer isextracted with EtOAc (3×5 L). The combined organic layer is washed withbrine (2 L), dried over anhydrous Na₂SO₄ and concentrated in vacuo. Thecrude oil is distilled to give the desired product. Yield: 1.6 kg. ¹HNMR: (CDCl₃) δ 4.31 (s, 2H), 4.23 (q, J=7.2 Hz, 2H), 4.19 (s, 2H), 2.47(t, J=2.4 Hz, 1H), 1.29 (t, J=7.2 Hz, 3H).

D-01B) (2-Oxo-propoxy)-acetic acid methyl ester

Hg(OAc)₂ (385 g, 1.1 mol) is added into a solution of D-01A (1.56 kg,11.0 mol) in MeOH (10 L) in portions and next conc. H₂SO₄ (55 mL) isadded dropwise. The mixture is refluxed for 1 h. After cooling to RT,the reaction mixture is concentrated in vacuo to a volume of 4 L. HCl(1M, 4.25 L) is added and the aqueous layer is extracted with DCM (5×3L). The combined organic layer is dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give a crude product (1.8 kg) which isdistilled in vacuo to give the title compound. Yield: 1.2 kg.

D-01C) 5-Hydroxy-6H-pyran-3-one

A solution of D-01B (1.04 kg, 6.5 mol) in anhydrous Et₂O (20 L) is addeddropwise over 2 h to a solution of t-BuOK (680 g, 6.07 mol) in t-BuOH (7L) and Et₂O (10 L) at rt. After stirring for 2 h, HCl (2M, 4 L) isadded. The layers are separated and the aqueous layer is extracted withEtOAc (2×10 L). The combined organic layer is washed with brine (2×4 L),dried over anhydrous Na₂SO₄ and concentrated in vacuo (below 35° C.) togive crude oil (600 g). The crude product is recrystallized fromEtOAc/petroleum ether (1:1) to afford the desired product. Yield: 152 g.¹H NMR: (DMSO-d₆) δ 11.80 (brs, 1H), 5.30 (s, 1H), 4.12-3.87 (s, 4H).

D-01D) 2-Amino-4H-pyrano[3,4-d]thiazol-7-one

D-01C (75.0 g 0.658 mol) and NaOAc (81.0 g 0.988 mol) are suspended inAcOH (750 mL). Br₂ (105.0 g 0.656 mol) is added dropwise whilemaintaining the reaction temperature between 15 to 20° C. The reactionis then allowed to stir at RT for 2 h. Thiourea (50.0 g 0.658 mol) isadded and the mixture heated at 100° C. overnight. The AcOH is removedin vacco and the residue is washed with water and hot EtOAc. Afterdrying in vacuo, the desired product is obtained as a gray powder.Yield: 50 g. ¹H NMR: (DMSO-d₆) δ 8.43 (brs, 2H) 4.64 (s, 2H) 4.11 (s,2H).

Compound D-01D (50.0 g, 0.294 mol) is added to Ac₂O (700 mL) and themixture is heated at 100° C. for 5 h. The reaction solution is cooled toRT and the produced solid is collected by filtration, washed with AcOH,EtOAc and water to afford the desired product as a brown solid. Yield:46.5 g. ¹H NMR: (DMSO-d₆) δ 12.76 (br s, 1H), 4.82 (s, 2H), 4.21 (s,2H), 2.18 (s, 3H).

D-02)1,1-Dimethyl-3-(7-oxo-6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl)-urea

To a suspension of D-01D (8.0 g, 47 mmol) in 45 mL acetonitrile is addedN,N′-carbonyl-di-imidazole (13.7 g, 84.6 mmol) and 1,8-DBU (6.33 g, 42.3mmol). The reaction mixture is stirred over night at 100° C. 2 Mdimethylamine solution in THF (47.0 mL, 94 mmol) is added and stirringis continued over night at 100° C. The reaction mixture is evaporatedand the residue is poured into ice-water. The pH of the mixture isadjusted to pH 5 with 6 M HCl solution. The aqueous mixture is extractedtwice with ethylacetate (150 mL each). The combined organic layers aredried over MgSO₄ and evaporated under reduced pressure. The crudeproduct is purified via column chromatography (silica, 0-20% EtOH inDCM). Yield: 3.7 g. (M+H)⁺: 242.

D-03) N-(7-oxo-6,7-dihydro-4H-thiopyrano[3,4-d]thiazol-2-yl)-acetamide

D-03A) (2-Oxo-propylsulfanyl)-acetic acid methyl ester

To a mixture of a 5.4 M methanolic solution of sodium methylate (185 mL,1.00 mol) in 500 mL methanol is added mercapto-acetic acid methyl ester(97.0 g, 912 mmol) at RT. After stirring for 20 minutes at RT chloroacetone (80 mL, 1.0 mmol) is added carefully. After complete additionthe reaction mixture is heated at reflux for 20 minutes. The reactionmixture is added to water and extracted with diethyl ether. The organiclayer is washed with brine, dried over Na₂SO₄ and the solvent isevaporated under reduced pressure. The crude reaction product isdistilled under reduced pressure (75° C.-90° C., 0.3 mbar) yielding thedesired product as colorless liquid. Yield: 61.5 g. (M+H)⁺=163

D-03B) 5-Hydroxy-6H-thiopyran-3-one

To sodium hydride (13.6 g, 340 mmol) in 800 mL THF at −10° C. is addeddropwise D-03A (50.0 g, 308 mmol) in 1 L THF. After complete additionthe reaction mixture is allowed to come to RT and stirring is continuedfor 3 hours. The formed precipitation is filtered off and dissolved in200 mL water. The aqueous solution is extracted with diethyl ether,acidified with 2 N HCl solution (pH 2) and extracted five times withCHCl₃ (200 mL each). The combined CHCl₃ phases are washed with brine,dried over Na₂SO₄ and the solvent is evaporated under reduced pressure.The product is recrystallized from diethylether yielding the desiredproduct as pale yellow solid. Yield: 15 g.

D-03C) 4-Bromo-5-hydroxy-6H-thiopyran-3-one

To a suspension of D-03B (39.0 g, 300 mmol) in 80 mL water is addeddropwise Br₂ (15.4 mL, 300 mol). The reaction mixture is stirred for 1hour at RT. The precipitate is filtered off. The residue is trituratedwith water, washed with diethyl ether, dried under reduced pressure andused as such in the next step. Yield: 45.2 g.

D-03D) 2-Amino-4H-thiopyrano[3,4-d]thiazol-7-one

A reaction mixture of D-03C (45.2 g, 216 mmol) and thiourea (18.0 g, 237mmol) in 400 mL ethanol is stirred under reflux for 4 hours. Thereaction mixture is diluted with methanol and the insoluble material isfiltered off. The residue is taken up in DMSO and added to water. Theformed precipitate is filtered off, washed with methanol and diethylether and dried in vacuo. Yield: 27.1 g. (M+H)⁺=187.

A suspension of D-03D in acetic anhydride is refluxed for 6 hours. Aftercooling to RT diethyl ether is added, the insoluble material is filteredoff and washed with water. The crude product is taken up in DMSO andadded dropwise to water. The precipitate is filtered off, washed withmethanol and water and dried in vacuo. Yield: 29.2 g. (M+H)⁺=229.

D-04)N-[7-Oxo-6-(2,2,2-trifluoro-acetyl)-6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl]-acetamide

D-04 is prepared using general procedure A3 starting from D-01 (1.00 g,4.71 mmol) and trifluoroacetyl imidazole (1.20 mL, 10.5 mmol, Aldrich).The reaction is worked-up with DCM and the product is purified by flashcolumn chromatography (silica gel, 0-20% EtOH in DCM). Yield: 223 mg.HPLC: t_(R)=2.98 min.

D-05)N-(6-Cyclopropanecarbonyl-7-oxo-6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl)-acetamide

D-05 is prepared using general procedure A2 starting from D-01 (1.00 g,4.71 mmol) and cyclopropanecarboxylic acid ethyl ester (2.30 mL, 19.0mmol). The reaction is worked-up by adding 1.8 mL acetic acid and 40 mLaqueous NaCl solution (half saturated) to the reaction mixture. Aftercooling to 0° C. and stirring the precipitated product is filtered off,washed with water and dried. Yield: 993 mg. HPLC-MS: t_(R)=1.08/1.30 min(Keto-Enol), (M+H)⁺=281.

D-06)N-[7-Oxo-6-(pyridine-3-carbonyl)-6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl]-acetamide

D-06 is prepared using general procedure A3 starting from D-01 (1.15 g,5.42 mmol) and nicotinic acid (1.33 g, 10.8 mmol). The reaction isworked-up with DCM and the product is purified by flash columnchromatography (silica gel, 0-20% EtOH in DCM). The desired product wasused without further purification in the next step.

D-07)N-[6-(6-Methoxy-pyridine-3-carbonyl)-7-oxo-6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl]-acetamide

D-07 is prepared using general procedure A2 starting from D-01 (3.00 g,14.1 mmol) and methyl 6-methoxynicotinate (3.70 g, 21.7 mmol). Theproduct is used in the next step without further purification. Yield:3.70 g. HPLC-MS: t_(R)=1.34 min, (M+H)⁺=348.

D-08)N-(6-Formyl-7-oxo-6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl)-acetamide

D-08 is prepared using general procedure A2 starting from D-01 (1.18 g,5.56 mmol) and formic acid ethyl ester (9.44 g, 111 mmol). The productis used in the next step without further purification. Yield: 863 mg.

D-09)N-[6-(6-Fluoro-pyridine-3-carbonyl)-7-oxo-6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl]-acetamide

D-09 is prepared via general procedure A1 starting from D-01 (1.00 g,4.71 mmol) and 2-fluoropyridine-5-carbonyl chloride (958 mg, 6.00 mmol).The crude product is used in the next step without further purification.Yield: 1.18 g.

D-10)[5-(2-Acetylamino-7-oxo-6,7-dihydro-4H-pyrano[3,4-d]thiazole-6-carbonyl)-pyridin-2-yl]ethyl-carbamicacid tert-butyl ester

D-10 is prepared via general procedure A1 starting from D-01 (265 mg,1.24 mmol) and (5-chlorocarbonyl-pyridin-2-yl)-ethyl-carbamic acidtert-butyl ester (A-09) (500 mg, 1.75 mmol). The product is used in thenext step without further purification.

Yield: 600 mg.

D-11)[5-(2-Acetylamino-7-oxo-6,7-dihydro-4H-pyrano[3,4-d]thiazole-6-carbonyl)-pyridin-2-yl]-methyl-carbamicacid tert-butyl ester

D-11 is prepared via general procedure A1 starting from D-01 (6.55 g,30.9 mmol) and (5-chlorocarbonyl-pyridin-2-yl)-methyl-carbamic acidtert-butyl ester (A-10) (10.7 g, 39.5 mmol). The product is purified byflash column chromatography (silica gel, 0-80% ethyl acetate incyclohexane). Yield: 2.0 g.

D-12){5-[2-(3,3-Dimethyl-ureido)-7-oxo-6,7-dihydro-4H-pyrano[3,4-d]thiazole-6-carbonyl]-pyridin-2-yl}-ethyl-carbamicacid tert-butyl ester

D-12 is prepared via general procedure A1 starting from D-02 (1.71 g,7.11 mmol) and (5-chlorocarbonyl-pyridin-2-yl)-ethyl-carbamic acidtert-butyl ester (A-09) (1.35 g, 4.74 mmol). The crude product is usedwithout further purification in the next step.

Yield: 1.3 g.

D-13)N-[7-Oxo-6-(pyridine-3-carbonyl)-6,7-dihydro-4H-thiopyrano[3,4-d]thiazol-2-yl]-acetamide

D-13 is prepared using general procedure A3 starting from D-03 (200 mg,0.87 mmol) and nicotinic acid (160 mg, 1.31 mmol). The crude product isused without further purification in the next step. Yield: 180 mg.

D-14)N-[6-(6-Methyl-pyridine-3-carbonyl)-7-oxo-6,7-dihydro-4H-thiopyrano[3,4-d]thiazol-2-yl]-acetamide

D-14 is prepared using general procedure A3 starting from D-03 (1.00 g,4.38 mmol) and 6-methyl nicotinic acid (900 mg, 6.57 mmol). The productis purified by flash column chromatography (silica gel, 0-20% MeOH inDCM). Yield: 1.1 g.

D-15)N-(6-Formyl-7-oxo-6,7-dihydro-4H-thiopyrano[3,4-d]thiazol-2-yl)-acetamide

To a solution of D-03 (10.0 g, 77 mmol) in 50 mL DMSO is added sodiumtert-pentoxide (14.4 g, 131 mmol). The reaction mixture is stirred for30 min at RT, cooled to 10° C. and a solution of ethyl formate (5.3 mL,66 mmol) in 20 mL DMSO is added dropwise. After complete addition thereaction mixture is stirred for 6 hours at RT. The reaction mixture ispoured into 200 mL cold water. Acetic acid is added at 10° C.-15° C.until pH 5 is reached. The mixture is extracted with ethyl acetate. Thecombined ethyl acetate layers are washed with brine and dried overNa₂SO₄. After evaporation of the solvent under reduced pressure thedesired product is obtained, which is used without further purificationin the next step.

Yield: 5.8 g.

D-16) (7-Oxo-6,7-dihydro-4H-thiopyrano[3,4-d]thiazol-2-yl)-carbamic acidmethyl ester

To a suspension of D-03d (34.1 g, 183 mmol) in 2.5 L THF sodiumtert-pentoxide (30.2 g, 275 mmol) is added at RT. Afterwards methylchloroformate (21.1 mL, 275 mmol) is added at 50° C. and stirring iscontinued for 3 hours at reflux. The reaction mixture is evaporated andtaken up in ethyl acetate and brine. The organic layer is dried overNa₂SO₄ and the solvent is evaporated under reduced pressure to give thedesired product.

Yield: 25.2. (M+H)⁺: 245.

D-17)(6-Formyl-7-oxo-6,7-dihydro-4H-thiopyrano[3,4-d]thiazol-2-yl)-carbamicacid methyl ester

To a solution of D-16 (9.5 g, 38.9 mmol) in 50 mL DMSO is added sodiumtert-pentoxide (12.9 g, 117 mmol). The reaction mixture is stirred for30 min at RT, cooled to 10° C. and a solution of ethyl formate (3.6 mL,58 mmol) in 20 mL DMSO is added dropwise. After complete addition thereaction mixture is stirred for 6 hours at RT. The reaction mixture ispoured into 200 mL cold water. Acetic acid is added at 10° C.-15° C.until pH 5 is reached. The mixture is extracted with ethyl acetate. Thecombined ethyl acetate layers are washed with brine and dried overNa₂SO₄. After evaporation of the solvent under reduced pressure thedesired product is obtained which is used without further purificationin the next step.

Yield: 5.3 g.

Examples E

Examples E-01 to E-42 are synthesized according to general procedure B.The appropriate hydrazine and diketone required for synthesis can bededuced from the table of examples.

TABLE 3 Examples E01-E42 No. MOLSTRUCTURE Diketone Hydrazine t_(R)(min.) (M + H)⁺ E-01

D-04 2-chloro phenyl hydrazine 3.24 415/417 E-02

D-04 2-bromo-phenyl hydrazine 3.24 459/461 E-03

D-04 2-trifluormethyl phenyl hydrazine 3.25 449 E-04

D-04 phenyl hydrazine 381 E-05

D-06 2-chloro phenyl hydrazine E-06

D-08 methyl hydrazine 0 251 E-07

D-09 2-bromo phenyl hydrazine 1.46 486/488 E-08

D-10 2-bromo phenyl hydrazine 1.46 511/513 E-09

D-10 isopropyl hydrazine 1.43 399 E-10

D-12 isopropyl hydrazine 428 E-11

D-12 2-bromo phenyl hydrazine 1.49 540/542 E-12

D-11 isopropyl hydrazine 1.42 385 E-13

D-13 (4-hydrazino- benzyl)-dimethyl- amine 463 E-14

D-13 3-chloro-4- hydrazino-N,N- dimethyl- benzamide 1.63 511 E-15

D-06 3-chloro-4- hydrazino- benzoic acid methyl ester 2.45 482/484 E-16

D-14 4-hydrazino- benzaldehyde O- methyl-oxime 2.08 477 E-17

D-13 isopropyl hydrazine 1.73 372 E-18

D-13 cyclopentyl hydrazine 1.94 398 E-19

D-13 cyclohexyl hydrazine 2.00 412 E-20

D-13 tert-butyl hydrazine 1.86 386 E-21

D-13 ethyl hydrazine 1.61 358 E-22

D-13 methyl hydrazine 1.57 344 E-23

D-15 isopropyl hydrazine 253 E-24

D-15 isopropyl hydrazine 1.66 295 E-25

D-15 cyclohexyl hydrazine 1.96 335 E-26

D-15 methyl hydrazine 1.37 267 E-27

D-15 cyclobutyl hydrazine 1.78 307 E-28

D-17 isopropyl hydrazine 1.73 311 E-29

D-17 cyclopentyl hydrazine 1.99 337 E-30

D-14 cyclohexyl hydrazine 2.08 426 E-31

D-14 2-chloro phenyl hydrazine 1.94 454/456 E-32

D-14 methyl hydrazine 1.66 358 E-33

D-14 o-tolyl hydrazine 1.97 434 E-34

D-14 phenyl hydrazine 1.94 420 E-35

D-14 3-chloro-4- hydrazino-N,N- dimethyl- benzamide 1.78 525 E-36

D-14 tert-butyl hydrazine 1.84 400 E-37

D-17 cyclohexyl hydrazine 2.05 351 E-38

D-17 cyclobutyl hydrazine 1.87 323 E-39

D-17 methyl hydrazine 1.45 283 E-40

D-06 4-hydrazino- cyclohexanecar- boxylic acid ethyl ester 1.22 468 E-41

D-07 4-hydrazino- cyclohexanecar- boxylic acid ethyl ester 1.43 498 E-42

D-05 4-hydrazino- cyclohexanecar- boxylic acid ethyl ester 1.44 431

Examples F

Examples F-01 to F-04 are synthesized according to the following generalprocedure. The appropriate starting material required for synthesis canbe deduced from the table of examples.

General Procedure F

A mixture of corresponding ester (1.00 mmol) and lithium hydroxide monohydrate (10.0 mmol) in 20 mL THF and 5 mL water is stirred at over nightat RT. The reaction mixture is acidified with acetic acid and dilutedwith water. THF is evaporated under reduced pressure. The precipitatedproduct is filtered off, washed with water and used without furtherpurification in the next step.

TABLE 4 Examples F01-F04 No. MOLSTRUCTURE Starting material t_(R) (min.)(M + H)⁺ F-01

E-15 2.24 486/470 F-02

E-40 1.08 440 F-03

E-41 1.23 470 F-04

E-42 1.21 403

Examples G

Examples G-01 to G-09 are synthesized according to the following generalprocedure G. The appropriate starting materials required for thesynthesis can be deduced from the table of examples.

General Procedure G

The corresponding acid (1 eq.) is taken up in DMA or DMF, DIPEA (4 eq.)and HATU (1.3 eq.) are added and the reaction mixture is stirred for 10min at RT. Amine is added and the reaction mixture is stirred overnightat RT followed by 1 h at 55° C. if necessary. The desired product iseither precipitated from the reaction mixture or aqueous potassiumcarbonate solution is added and the resultant mixture is extracted withDCM and purified by HPLC (C18, 5-98% acetonitrile in water containing0.1% formic acid or MeOH/water and TFA).

TABLE 5 Examples G01-G09 No. MOLSTRUCTURE Acid Amine t_(R) (min.) (M +H)⁺ G-01

F-01 4-pyrrolidin-1-yl- cyclohexylamine 618/620 G-02

F-04 dimethyl amine 1.22 430 G-03

F-04 methyl-(4- pyrrolidin-1-yl- cyclohexyl)-amine 1.18 567 G-04

F-02 ((R)-1- Cyclopentyl- pyrrolidin-3-yl)- methyl-amine 1.08 590 G-05

F-02 dimethyl amine 1.09 467 G-06

F-02 Methyl-(4- pyrrolidin-1-yl cyclohexyl)-amine 1.06 604 G-07

F-03 Methyl-(4- pyrrolidin-1-yl- cyclohexyl)-amine 634 G-08

F-03 Methyl-(4- pyrrolidin-1-yl- cyclohexyl)-amine G-09

F-03 Methyl-(4-methyl- 4-pyrrolidin-1-yl- cyclohexyl)-amine 648Analytical Method 1

HPLC: Agilent 1100 Series MS: Agilent LC/MSD SL column: Phenomenex,Mercury Gemini C18, 3 μm, 2.0 × 20 mm, Part.No. 00M-4439-B0-CE solventA: 5 mM NH₄HCO₃/ 20 mM NH₃ B: acetonitrile HPLC grade detection: MS:Positive and negative mass range: 120-700 m/z fragmentor: 70 gain EMV: 1threshold: 150 stepsize: 0.25 UV: 315 nm bandwidth: 170 nm reference:off range: 210-400 nm range step: 2.00 nm peakwidth: <0.01 min slit: 2nm injection: 5 μL flow: 1.00 mL/min column temperature: 40° C.gradient: 0.00 min  5% B 0.00-2.50 min  5% -> 95% B 2.50-2.80 min 95% B2.81-3.10 min 95% -> 5% BAbbreviations Used

bu butyl tert tertiary d day(s) THF tetrahydrofuran DC thin layerchromatography LiHMDS Lithium hexamethyl disilazide DCM dichloromethaneiPr isopropyl DMF N,N-dimethylformamide MTBE tertiary butylmethyletherDMSO dimethylsulphoxide NP normal phase et ethyl CDI carbonyldiimidazole h hour(s) ACN acetonitrile HPLC high performance liquidBINAP 2R,3S,2,2′-bis-(diphenyl-phosphino)- chromatography 1,1′-binapthylM molar DIPEA diisopropylethyl amine me methyl min minute(s) DCE1,2-dichloroethane mL milliliter NMP N-methylpyrrolindinone MS massspectrometry prep preparative N normal conc. concentrated NMR nuclearresonance TFA trifluoroacetic acid spectroscopy ppm part per millionHATU N-[(dimethylamino)-(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)-methylene]- N-methylmethan-aminiumhexafluorophosphate N-oxide R_(f) retention factor DMAN,N-dimethylacetamide RP reversed phase TBTUO-(Benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium tetrafluoroborate RTroom temperature PEPPSI [1,3-Bis(2,6-Diisopropylphenyl)-imidazol-2-ylidene](3-chloro-pyridyl) palladium(II) dichloride t_(R)retention time m.p. melting point DMAP dimethyl-pyridin-4-yl-amine DBU1,8-diazabicyclo[5.4.0]undec-7-ene

The Examples that follow describe the biological activity of thecompounds according to the invention without restricting the inventionto these Examples.

PC3 Proliferation Test

The test is based on measurement of cellular DNA content via fluorescentdye binding. Because cellular DNA content is highly regulated, it isclosely proportional to cell number. The extent of proliferation isdetermined by comparing cell counts for samples treated with drugs withuntreated controls.

PC3 (human prostate carcinoma cell line) cells are sown in microtitreplates and incubated overnight in culture medium at 37° C. and 5% CO₂.The test substances are diluted stepwise and added to the cells suchthat the total volume is 200 μL/well. Cells to which diluent, but notsubstance, is added serve as controls. After an incubation time of 3days, the medium is replaced by 100 μL/well dye-binding solution and thecells are incubated at 37° C. in the dark for a further 60 min. Formeasuring the fluorescence, excitation takes place at a wavelength of485 nm and the emission is measured at 530 nm.

EC₅₀ values are calculated using the GraphPad Prism program.

Most compounds of the Examples cited have an EC₅₀ (Proliferation PC3) ofless than 5.0 μM.

P-AKT Measurement in PC3 Cells

P-AKT levels in PC3 cells are detected by cell-based ELISA. Cells arecultured in 96-well plates and treated with serial dilutions of testsubstances for 2 h. Cells to which diluent, but not substance, is addedserve as controls. Subsequently, the cells are fixed rapidly topre-serve protein modifications. Each well is then incubated with aprimary antibody specific for Ser473-phosphorylated AKT. Subsequentincubation with secondary HRP-conjugated antibody and developingsolution provides a colorimetric readout at 450 nm. EC₅₀ values arecalculated using the GraphPad Prism program.

Most compounds of the Examples cited have an EC₅₀ (P-AKT PC3) of lessthan 1.0 μM.

The substances of the present invention are PI3 kinase inhibitors. Onaccount of their biological properties, the novel compounds of thegeneral formula (1) and their isomers and their physiologicallytolerated salts are suitable for treating diseases which arecharacterized by excessive or anomalous cell proliferation.

These diseases include, for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammation and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphomas andsolid tumours; skin diseases (e.g. psoriasis); bone diseases;cardiovascular diseases (e.g. restenosis and hypertrophy). In addition,the compounds are useful for protecting proliferating cells (e.g. haircells, intestinal cells, blood cells and progenitor cells) from DNAdamage due to irradiation, UV treatment and/or cytostatic treatment(Davis et al., 2001).

For example, the following cancers may be treated with compoundsaccording to the invention, without being restricted thereto:

brain tumours such as for example acoustic neurinoma, astrocytomas suchas fibrillary, protoplasmic, gemistocytary, anaplastic, pilocyticastrocytomas, glioblastoma, gliosarcoma, pleomorphic xanthoastrocytoma,subependymal large-cell giant cell astrocytoma and desmoplasticinfantile astrocytoma; brain lymphomas, brain metastases, hypophysealtumour such as prolactinoma, hypophyseal incidentaloma, HGH (humangrowth hormone) producing adenoma and corticotrophic adenoma,craniopharyngiomas, medulloblastoma, meningeoma and oligodendroglioma;nerve tumours such as for example tumours of the vegetative nervoussystem such as neuroblastoma, ganglioneuroma, paraganglioma(pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumourson the peripheral nervous system such as amputation neuroma,neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignantSchwannoma, as well as tumours of the central nervous system such asbrain and bone marrow tumours; intestinal cancer such as for examplecarcinoma of the rectum, colon, anus and duodenum; eyelid tumours(basalioma or adenocarcinoma of the eyelid apparatus); retinoblastoma;carcinoma of the pancreas; carcinoma of the bladder; lung tumours(bronchial carcinoma-small-cell lung cancer (SCLC), non-small-cell lungcancer (NSCLC) such as for example spindle-cell plate epithelialcarcinomas, adenocarcinomas (acinary, paillary, bronchiolo-alveolar) andlarge-cell bronchial carcinoma (giant cell carcinoma, clear-cellcarcinoma)); breast cancer such as ductal, lobular, mucinous or tubularcarcinoma, Paget's carcinoma; non-Hodgkin's lymphomas (B-lymphatic orT-lymphatic NHL) such as for example hair cell leukaemia, Burkitt'slymphoma or mucosis fungoides; Hodgkin's disease; uterine cancer (corpuscarcinoma or endometrial carcinoma); CUP syndrome (Cancer of UnknownPrimary); ovarian cancer (ovarian carcinoma—mucinous or serous cystoma,endometriodal tumours, clear cell tumour, Brenner's tumour); gallbladder cancer; bile duct cancer such as for example Klatskin tumour;testicular cancer (germinal or non-germinal germ cell tumours);laryngeal cancer such as for example supra-glottal, glottal andsubglottal tumours of the vocal cords; bone cancer such as for exampleosteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma,chondrosarcoma, osteoma, osteoid osteoma, osteoblastoma, osteosarcoma,non-ossifying bone fibroma, osteofibroma, desmoplastic bone fibroma,bone fibrosarcoma, malignant fibrous histiocyoma, osteoclastoma or giantcell tumour, Ewing's sarcoma, and plasmocytoma, head and neck tumours(HNO tumours) such as for example tumours of the lips, and oral cavity(carcinoma of the lips, tongue, oral cavity), nasopharyngeal carcinoma(tumours of the nose, lymphoepithelioma), pharyngeal carcinoma,oropharyngeal carcinomas, carcinomas of the tonsils (tonsil malignoma)and (base of the) tongue, hypopharyngeal carcinoma, laryngeal carcinoma(cancer of the larynx), tumours of the paranasal sinuses and nasalcavity, tumours of the salivary glands and ears; liver cell carcinoma(hepatocellular carcinoma (HCC); leukaemias, such as for example acuteleukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acutemyeloid leukaemia (AML); chronic lymphatic leukaemia (CLL), chronicmyeloid leukaemia (CML); stomach cancer (papillary, tubular or mucinousadenocarcinoma, adenosquamous, squamous or undifferentiated carcinoma;malignant melanomas such as for example superficially spreading (SSM),nodular (NMM), lentigo-maligna (LMM), acral-lentiginous (ALM) oramelanotic melanoma (AMM); renal cancer such as for example kidney cellcarcinoma (hypernephroma or Grawitz's tumour); oesophageal cancer;penile cancer; prostate cancer; vaginal cancer or vaginal carcinoma;thyroid carcinomas such as for example papillary, follicular, medullaryor anaplastic thyroid carcinoma; thymus carcinoma (thymoma); cancer ofthe urethra (carcinoma of the urethra, urothelial carcinoma) and cancerof the vulva.

The novel compounds can be used for the prevention or short-term orlong-term treatment of the abovementioned diseases including, whereappropriate, in combination with other state-of-the-art compounds suchas other anti-tumour substances, cytotoxic substances, cellproliferation inhibitors, antiangiogenic substances, steroids orantibodies.

The compounds of the general formula (1) can be used on their own or incombination with other active compounds according to the invention and,where appropriate, in combination with other pharmacologically activecompounds as well. Chemotherapeutic agents which can be administered incombination with the compounds according to the invention include,without being restricted thereto, hormones, hormone analogs andantihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant,megestrol acetate, flutamide, nilutamide, bicalutamide,aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate,fludrocortisone, fluoxymesterone, medroxyprogesterone and octreotide),aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole,exemestane and atamestane), LHRH agonists and antagonists (e.g.goserelin acetate and luprolide), inhibitors of growth factors (growthfactors such as platelet-derived growth factor and hepatocyte growthfactor, examples of inhibitors are growth factor antibodies, growthfactor receptor antibodies and tyrosine kinase inhibitors, such asgefitinib, imatinib, lapatinib, Erbitux® and trastuzumab);antimetabolites (e.g. antifolates such as methotrexate and raltitrexed,pyrimidine analogs such as 5-fluorouracil, capecitabine and gemcitabine,purine and adenosine analogs such as mercaptopurine, thioguanine,cladribine and pentostatin, cytarabine and fludarabine); antitumourantibiotics (e.g. anthracyclines, such as doxorubicin, daunorubicin,epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin,plicamycin and streptozocin); platinum derivatives (e.g. cisplatin,oxaliplatin and carboplatin); alkylating agents (e.g. estramustine,meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine,cyclophosphamide, ifosfamide and temozolomide, nitrosoureas such ascarmustine and lomustine and thiotepa); antimitotic agents (e.g. vincaalkaloids such as vinblastine, vindesine, vinorelbine and vincristine;and taxans such as paclitaxel and docetaxel); topoisomerase inhibitors(e.g. epipodophyllotoxins such as etoposide and etopophos, teniposide,amsacrine, topotecan, irinotecan and mitoxantrone) and variouschemotherapeutic agents such as amifostin, anagrelide, clodronate,filgrastin, interferon alpha, leucovorin, rituximab, procarbazine,levamisole, mesna, mitotan, pamidronate and porfimer.

Examples of suitable forms for use are tablets, capsules, suppositories,solutions, in particular solutions for injection (s.c., i.v., i.m.) andinfusion, syrups, emulsions or dispersible powders. In this connection,the proportion of the pharmaceutically active compound(s) should in eachcase be in the range of 0.1-90% by weight, preferably 0.5-50% by weight,of the total composition, that is in quantities which are sufficient toachieve the dosage range which is specified below. If necessary, thedoses mentioned can be given several times a day.

Appropriate tablets can be obtained, for example, by mixing the activecompound(s) with known auxiliary substances, for example inert diluents,such as calcium carbonate, calcium phosphate or lactose, disintegrants,such as maize starch or alginic acid, binders, such as starch orgelatine, lubricants, such as magnesium stearate or talc, and/or agentsfor achieving a depot effect, such as carboxymethyl cellulose, celluloseacetate phthalate or polyvinyl acetate. The tablets can also compriseseveral layers.

Correspondingly, sugar-coated tablets can be produced by coating cores,which have been prepared in analogy with tablets, with agents which arecustomarily used in sugar coatings, for example collidone or shellac,gum arabic, talc, titanium dioxide or sugar. The core can also compriseseveral layers in order to achieve a depot effect or to avoidincompatibilities. In the same way, the sugar coating can also compriseseveral layers in order to achieve a depot effect, with it beingpossible to use the auxiliary substances which are mentioned above inthe case of the tablets.

Syrups of the active compounds or active compound combinations accordingto the invention can additionally comprise a sweetening agent, such assaccharine, cyclamate, glycerol or sugar as well as a taste-improvingagent, e.g. flavouring agents such as vanillin or orange extract. Theycan also comprise suspension aids or thickeners, such as sodiumcarboxymethyl cellulose, wetting agents, for example condensationproducts of fatty alcohols and ethylene oxide, or protectants such asp-hydroxybenzoates.

Injection and infusion solutions are produced in a customary manner,e.g. while adding isotonizing agents, preservatives, such asp-hydroxybenzoates, or stabilizers, such as alkali metal salts ofethylenediaminetetraacetic acid, where appropriate using emulsifiersand/or dispersants, with it being possible, for example, to employ,where appropriate, organic solvents as solubilizing agents or auxiliarysolvents when using water as diluent, and aliquoted into injectionbottles or ampoules or infusion bottles.

The capsules, which comprise one or more active compounds or activecompound combinations, can, for example, be produced by mixing theactive compounds with inert carriers, such as lactose or sorbitol, andencapsulating the mixture in gelatine capsules. Suitable suppositoriescan be produced, for example, by mixing with excipients which areenvisaged for this purpose, such as neutral fats or polyethylene glycol,or their derivatives.

Auxiliary substances which may be mentioned by way of example are water,pharmaceutically unobjectionable organic solvents, such as paraffins(e.g. petroleum fractions), oils of vegetable origin (e.g. groundnut oilor sesame oil), monofunctional or poly-functional alcohols (e.g. EtOH orglycerol), carrier substances such as natural mineral powders (e.g.kaolins, argillaceous earths, talc and chalk), synthetic mineral powders(e.g. highly disperse silicic acid and silicates), sugars (e.g. canesugar, lactose and grape sugar), emulsifiers (e.g. lignin, sulphitewaste liquors, methyl cellulose, starch and polyvinyl-pyrrolidone) andglidants (e.g. magnesium stearate, talc, stearic acid and sodium laurylsulphate).

Administration is effected in a customary manner, preferably orally ortransdermally, in particular and preferably orally. In the case of oraluse, the tablets can naturally also comprise, in addition to theabovementioned carrier substances, additives such as sodium citrate,calcium carbonate and dicalcium phosphate together with a variety offurther substances such as starch, preferably potato starch, gelatineand the like. It is furthermore also possible to use glidants, such asmagnesium stearate, sodium lauryl sulphate and talc, for the tableting.In the case of aqueous suspensions, a variety of taste improvers or dyescan also be added to the active compounds in addition to theabovementioned auxiliary substances.

For parenteral administration, it is possible to employ solutions of theactive compounds while using suitable liquid carrier materials. Thedosage for intravenous administration is 1-1000 mg per hour, preferablybetween 5 and 500 mg per hour.

Despite this, it may be necessary, where appropriate, to diverge fromthe above-mentioned quantities, depending on the body weight or thenature of the route of administration, on the individual response to themedicament, on the nature of its formulation and on the time or intervalat which the administration is effected. Thus, it may, in some cases, besufficient to make do with less than the previously mentioned lowestquantity whereas, in other cases, the abovementioned upper limit has tobe exceeded. When relatively large quantities are being administered, itmay be advisable to divide these into several single doses which aregiven over the course of the day.

The following formulation examples illustrate the present inventionwithout, however, restricting its scope:

Pharmaceutical Formulation Examples

A) Tablets per tablet Active compound in accordance with formula (1) 100mg Lactose 140 mg Maize starch 240 mg Polyvinylpyrrolidone 15 mgMagnesium stearate 5 mg 500 mg

The finely ground active compound, lactose and a part of the maizestarch are mixed with each other. The mixture is sieved, after which itis moistened with a solution of polyvinyl-pyrrolidone in water, kneaded,wet-granulated and dried. The granular material, the remainder of themaize starch and the magnesium stearate are sieved and mixed with eachother. The mixture is pressed into tablets of suitable shape and size.

B) Tablets per tablet Active compound in accordance with formula (1) 80mg Lactose 55 mg Maize starch 190 mg Micro crystalline cellulose 35 mgPolyvinylpyrrolidone 15 mg Sodium carboxymethyl starch 23 mg Magnesiumstearate 2 mg 400 mg

The finely ground active compound, a part of the maize starch, thelactose, micro-crystalline cellulose and polyvinylpyrrolidone are mixedwith each other, after which the mixture is sieved and worked, togetherwith the remainder of the maize starch and water, into a granularmaterial, which is dried and sieved. The sodium carboxymethyl starch andthe magnesium stearate are then added to the granular material and mixedwith it, and the mixture is pressed into tablets of suitable size.

C) Ampoule solution Active compound in accordance with formula (1) 50 mgSodium chloride 50 mg Water for injection 5 mL

The active compound is dissolved, either at its intrinsic pH or, whereappropriate, at pH 5.5-6.5, in water after which sodium chloride isadded as isotonizing agent. The resulting solution is renderedpyrogen-free by filtration and the filtrate is aliquoted, under asepticconditions, into ampoules, which are then sterilized and sealed bymelting. The ampoules contain 5 mg, 25 mg and 50 mg of active compound.

The invention claimed is:
 1. A compound selected from the groupconsisting of: No. MOLSTRUCTURE B1

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or a salt thereof.
 2. A pharmacologically acceptable salt of a compoundaccording to claim
 1. 3. A pharmaceutical composition comprising acompound according to claim 1, or a pharmacologically acceptable saltthereof and a carrier or excipient.